The present invention relates to a pharmaceutical composition comprising glyceryl trinitrate for delivery in aerosol form and to a device for delivering such a composition as an aerosol.
Glyceryl trinitrate is well established in the treatment and prophylaxis of angina pectoris and, when used to relieve acute attacks, is most commonly administered lingually, sub-lingually or buccally in the form of a spray, buccal tablet or chewable lozenge. Absorption of glyceryl trinitrate via the oral mucosa, particularly the sub-lingual oral mucosa, is rapid and haemodynamic effects and relief from pain are almost immediate.
Current aerosol spray formulations of glyceryl trinitrate use one or more chlorofluorocarbon as a propellant; dichlorodifluoromethane being commonly used. However, chlorofluorocarbons have been implicated in the depletion of the ozone layer and their production, therefore, is being phased out. It as been found that certain hydrofluorocarbons, which are both of low toxicity and of suitable vapour pressure for use as aerosol propellants, are significantly less harmful to the ozone layer. Among such hydrofluorocarbons, 1,1,1,2-tetrafluoroethane (HFC-134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFC-227) have been proposed as suitable propellants for pharmaceutical aerosols.
It has now been found that HFC-134a and HFC-227 can be used in combination with glyceryl trinitrate, without causing any degradation of the latter or reduction in its physiological effect.
Devices for administering metered aerosol doses of pharmaceutical preparations are well known in the art. Such devices include those disclosed in WO 92/11190, U.S. Pat. No. 4,819,834, U.S. Pat. No. 4,407,481. Many of these devices include metering valves having components formed from plastic materials, such as the valves available from Bespak PLC of Bergen Way, Kings Lynn, Norfolk PE30 2JJ, United Kingdom, in which the valve core, metering chamber and some other structural components are formed from plastic materials. The plastic materials currently used for forming these structural parts in valves employed with chlorofluorocarbon containing formulations of glyceryl trinitrate include certain acetal co-polymers.
Although the plastics employed to manufacture metering valves, including the aforementioned acetal co-polymers, have also been found to be stable in the presence of HFC-134a alone, the applicants, to their surprise, have determined that many of these plastics materials can be caused to swell in the presence of formulations which include glyceryl trinitrate and HFC-134a. When such swelling takes place in a valve, the fit of mutually slidable components, such as metering chambers and valve cores, is adversely effected and they can bind together or become loose, causing the valve to leak or cease functioning altogether.